Total synthesis of (–)-brazilane via a lipase-catalyzed desymmetrisation reaction

Article abstract of DOI:10.1080/14786419.2021.1922403

Herein, we described the asymmetric total synthesis of (–)-brazilane, an optically active natural product. The key steps of this synthetic approach are a lipase-catalyzed desymmetrisation reaction of a prochiral diol using vinyl acetate to prepare a chira

Full text of DOI:10.1080/14786419.2021.1922403

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Total synthesis of (–)-brazilane via a lipase-
catalyzed desymmetrisation reaction
Xiaofeng Guo, Zhiwei Xue, Dongdong Xu, Qidong Tu, Honghong Chang, Xihua
Yang & Shuangping Huang
To cite this article: Xiaofeng Guo, Zhiwei Xue, Dongdong Xu, Qidong Tu, Honghong Chang,
Xihua Yang & Shuangping Huang (2021): Total synthesis of (–)-brazilane via a lipase-catalyzed
desymmetrisation reaction, Natural Product Research, DOI: 10.1080/14786419.2021.1922403
To link to this article: https://doi.org/10.1080/14786419.2021.1922403
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2021.1922403
Total synthesis of (–)-brazilane via a lipase-catalyzed
desymmetrisation reaction
Xiaofeng Guoa, Zhiwei Xuea, Dongdong Xua, Qidong Tub, Honghong Changa,
Xihua Yangb and Shuangping Huangc
b
aCollege of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China; School of
Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi, P.R. China;
cLaboratory Animal Center, Shanxi Cancer Institute, Taiyuan, China
ABSTRACT
ARTICLE HISTORY
Received 17 December 2020
Accepted 22 April 2021
Herein, we described the asymmetric total synthesis of (–)-brazil-
ane, an optically active natural product. The key steps of this syn-
thetic approach are a lipase-catalyzed desymmetrisation reaction
of a prochiral diol using vinyl acetate to prepare a chiral primary
alcohol and a trifluoroacetic acid-catalyzed one pot intramolecular
tandem Prins/Friedel-Crafts reaction used to construct the cis-
fused chromane and indane framework.
KEYWORDS
Total synthesis;
(–)-brazilane; natural
product; lipase-catalyzed
desymmetrisation; tandem
Prins/Friedel-Crafts reaction
1. Introduction
Natural products containing a homoisoflavonoid skeleton possess novel biological activ-
ities and play an important role in pharmaceutical research and applications (Abegaz
et al. 2007). As important members of the homoisoflavonoid family of natural products,
tetracyclic brazilane and its related compounds (Figure 1) have demonstrated a series of
outstanding bioactivities. For example, brazilin shows anti-inflammatory (Bae et al.
2005), hypoglycemic (Moon et al. 1993; Kim et al. 1998), vasorelaxant (Hu et al. 2003),
antibacterial (Xu and Lee 2004), antitumor (Kim et al. 2012; Lee et al. 2013) and neuro-
ꢀ
protection activities (Liu et al. 2019; Henrıquez et al. 2020). Brazilane and its related
compounds (Figure 1) are found in the alcoholic extracts of heartwood of Caesalpinia
sappan L. (Legminosae), which is also a famous traditional Chinese medicine used for
treatment of emmeniopathy, convulsions, straumatic disease and menstrual disorders.
CONTACT Honghong Chang
changhonghong@tyut.edu.cn; Xihua Yang
yangxihua@126.com; Shuangping
Huang huangshuangping@tyut.edu.cn
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14786419.2021.1922403.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

2
X. GUO ET AL.
Figure 1. Structures of brazilane and some selected homoisoflavonoids.
Structurally, brazilane is the reduced counterpart of this family of compounds bearing
an H-atom instead of a hydroxyl group at the C-3 position. Our research interest has
focused on studying the structure-activity relationships of natural products and their
potential pharmaceutical properties through total synthesis. We have recently accom-
plished a novel synthetic approach to (þ)-brazilin employing a Sharpless asymmetric
dihydroxylation to introduce the chiral center and a one pot trifluoroacetic acid-cata-
lyzed intramolecular tandem Prins/Friedel-Craft reaction as the key steps (Huang et al.
2020). Considering that brazilane possesses the basic skeleton of its family of natural
products, the development of a practicable synthetic route to brazilane may inspire the
synthesis of other related family members or functionalised derivatives. To the best of
our knowledge, only three racemic total syntheses of brazilane (Lin et al. 2008; Yadav
et al. 2014; Kim and Kim 2018) and two semi-syntheses (Morsingh and Robinson 1970;
Xu and Yadan 1996) have been published to date with no asymmetric total synthesis
previously reported. Herein, we describe an efficient and practicable asymmetric syn-
thetic route to (–)-brazilane using a non-toxic enzymatic reaction as the key step.
Our retrosynthesis of brazilane is depicted in Scheme 1. We envisioned that (–)-bra-
zilane may arise from its O-methyl ether (1) via its deprotection (Kim and Kim 2018).
The cis-fused chromane and indane framework of 1 can be accessed via an intramo-
lecular tandem Prins/Friedel-Craft reaction from aldehyde 2 (Huang et al. 2020), which
can be obtained from intermediate 3 following a simple sequence of reactions.
Intermediate 3 was disconnected into 3-methoxyphenol and alcohol 4, while the ace-
tyl group in 4 can be assumed to be installed using a lipase-catalyzed desymmetrisa-
tion reaction of diol 5 (Kawasaki et al. 2013), which can be easily synthesised from 3,4-
dimethoxybenzyl alcohol (6).
Scheme 2 shows the synthesis was started from commercially available 3,4-dime-
thoxybenzyl alcohol (6). The hydroxyl group in 6 was converted into its corresponding
tosylate (7) upon reaction with tosyl chloride in the presence of triethylamine in
CH2Cl2 in 83% yield (Rosowsky et al. 1998). Diethyl malonate undergoes an SN2 reac-
tion with 7 using sodium hydride as base in a mixed solvent comprised of THF-DMF
(1:1) to give diethyl ester 8, in which the double ethyl ester groups were both reduced
using lithium aluminum hydride in dry THF at room temperature to afford diol 5 in

NATURAL PRODUCT RESEARCH
3
Scheme 1. Retrosynthetic analysis of (–)-brazilane.
Scheme 2. Reagents and conditions: (a) TsCl, Et3N, DMAP, DCM, r.t., 83%; (b) NaH, diethyl malonate,
ꢀ
ꢀ
THF-DMF (1:1), 0 C to r.t., 90%; (c) LiAlH4, THF, 0 C to r.t., 87%; (d) Lipase PS, vinyl acetate, r.t.,
99%, 96% ee; (e) 1,1’-(Azodicarbonyl)-dipiperidine, Bu3P, THF, 70 ꢀC, 87%; (f) K2CO3, MeOH, r.t.,
89%; (g) DMP, CH2Cl2, r.t, 83%.
87% yield (Itoh et al. 1993). Retrosynthetically, we needed to enantioselectively protect
one hydroxyl group in 5. Therefore, we performed the desymmetrisation reaction
using an enzymatic reaction (Kawasaki, et al. 2013). Treatment of diol 5 with lipase

4
X. GUO ET AL.
using vinyl acetate as the reagent/solvent at room temperature for 4 h furnished the
desired mono-protected alcohol (4) in an almost quantitative yield and 96% ee [chiral
analysis conditions: OJ-H column, hexane/2-propanol ¼ 4:1 (v/v), 0.5 mL/min, 254 nm].
The absolute configuration of 4 was assumed to be R on the basis of Kawasaki’s study
(Kawasaki, et al. 2013) and the configuration of the final product.
2. Results and discussion
Unfortunately, the next etherification reaction was problematic. None of the desired
ether (3) was obtained under conventional Mitzunobu reaction conditions using tri-
phenyl phosphine in the presence of diisopropyl azodicarboxylate (DIAP) or diethyl
azodicarboxylate (DEAD). According to Li’s observations (Huang et al. 2015), 1,10-(azo-
dicarbonyl)-dipiperidine (ADDP) was used in place of DIAD and DEAD. To our delight,
treating 4 and 3-methoxyphenol in the presence of ADDP and Bu3P in refluxing THF
gave the desired ether (3) in excellent yield (87%). Subsequently, the acetyl group was
readily removed upon treatment with K2CO3 in MeOH to release the alcohol group
and gave 9 in 89% yield, which smoothly undergoes a Dess-Martin oxidation reaction
to give aldehyde 2 in 83% yield.
With aldehyde 2 in hand, we next conducted the one pot intramolecular tandem
Prins/Friedel-Crafts reaction. We first used the conditions originally employed in the
synthesis of brazilin. However, the desired cyclisation product (1) was obtained in only
42% yield (Table 1, entry 1). We considered a stronger acid would more readily pro-
mote the cyclisation reaction, but unfortunately no obvious changes in the yield of 1
was observed when using trifluoromethanesulfonic acid (TfOH) as the catalyst (0.5 or 1
equiv) (entries 2 and 3). We also increased the amount of trifluoroacetic acid (TFA),
and only a slightly lower product yield was obtained (entry 4). Finally, we carried out
the cyclisation upon treatment with five equiv of p-toluenesulfonic acid (p-TsOH) at
room temperature for 1 h and the desired product was obtained in 51% yield as a sin-
gle isomer (entry 5), which was identical to our previous study (Huang et al. 2020). To
our surprise, compound 1 was found to unstable during our studies on the cyclisation
reaction and would decompose even upon storage at ꢁ15 ꢀC for a few hours. The low
product yield may be attributed to its instability. Therefore, 1 was immediately used in
the next demethylation step.
Table 1. Examination of the intramolecular tandem Prins/Friedel-Crafts reaction.
Entry
Reaction conditions
Yield of 9a
1
2
3
4
5
TFA (0.5 equiv), DCM, rt, 12 h
TfOH (0.5 equiv), MeCN, rt, 12 h
TfOH (1.0 equiv), MeCN, rt, 1 h
TFA (4.0 equiv), DCM, rt, 1 h
p-TsOH (5.0 equiv), DCM, rt, 1 h
42%
42%
40%
38%
51%
aYield based upon isolation of the product using silica gel column chromatography.

NATURAL PRODUCT RESEARCH
5
ꢀ
Scheme 3. Reagents and conditions: (h) BBr3, DCM, -78 C to r.t., 63%, 96% ee.
Finally, as shown in Scheme 3, the endgame for the synthesis of (–)-brazilane was
the removal of the methyl groups on the phenolic hydroxyl groups of intermediate 1
upon treatment with BBr3 according to a literature procedure (Kim and Kim 2018).
(–)-Brazilane was readily obtained in ꢂ63% yield (96% ee) under conventional depro-
tection conditions using BBr3, which also indicated that no racemisation occurred dur-
ing the Prins/Friedel-Crafts cyclisation. The physical and spectral data for the product
were identical to those reported in the literature (shown in Table S1 in supplemen-
tary material).
3. Experimental
3.1. General
All reactions were carried out under a N2 atmosphere and with dry solvents unless
otherwise noted. They were monitored by thin-layer chromatography (TLC) carried out
on 0.25 mm silica gel plates (60 F-254). Silica gel (200–300 mesh) used for flash column
chromatography was supplied by Qingdao Marine chemical factory in China.
Anhydrous tetrahydrofuran (THF), dichloromethane (DCM) and N, N-dimethyl forma-
mide (DMF) was supplied by Energy Chemical in China. Yield refers to that obtained
chromatographically and spectroscopically (1H, 13C NMR), unless otherwise stated.
1
NMR spectra were recorded on a Brucker AVANCE 400 spectrometer (400 MHz for H
NMR, 100 MHz for 13C NMR). High-resolution mass spectra were obtained using a
Waters Xevo G2-XS QTOF Mass Spectrometer. Chiral HPLC analyses were performed on
SHIMADZU LC-10A VP with a UV detector at wavelength k ¼ 254.0 nm and OJ-H
(15 cm ꢃ 0.5 cm) or Waters Acquity Upc2 with a UV detector at wavelength
k ¼ 214.0 nm and AD-H (15 cm ꢃ 0.5 cm) as the stationary phase. Melting points
(uncorrected) were determined with an electrothermal capillary melting point appar-
atus made by Tianjin optical instrument factory. Optical rotations were measured on a
digital polarimeter in MeOH or CH2Cl2 at 25 ꢀC.
3.2. Procedures
3.2.1. Diethyl 2-(3,4-dimethoxybenzyl)malonate (8)
DMAP (0.0872 g, 0.71 mmol), TsCl (0.2720 g, 1.43 mmol) and Et3N (0.17 mL, 1.19 mmol)
were added sequentially to a magnetically stirred solution of 6 (0.2 g, 1.19 mmol) in
anhydrous DCM (5 mL) under N2, The reaction mixture was stirred for 2 h at room

6
X. GUO ET AL.
temperature and quenched with H2O. The mixture was extracted with CH2Cl2
(3 ꢃ 6 mL). The combined organic layers were dried over Na2SO4, filtered, and concen-
trated under reduced pressure to provide a yellow oily residue, which was purified by
flash chromatography on silica gel (EtOAc/PE ¼ 1:10) to give compound 7 as an col-
ourless oil (0.32 g, 83% yield).
To a solution of sodium hydride (60% in mineral oil; 0.0513 g, 1.28 mmol) in anhyd-
rous DMF (2 mL) and THF (2 mL) was added a solution of diethyl malonate (0.24 mL,
1.60 mmol) in THF (2 mL) at 0 ꢀC and the mixture was stirred for 30 min at 0 ꢀC. To this
mixture was added an anhydrous THF (2 mL) solution of compound 7 (0.2 g,
1.07 mmol) at 0 ꢀC, followed by stirring at room temperature for 12 h. The mixture was
acidified by 2 M HC1 and extracted with EtOAc (3 ꢃ 5 mL). After distillation under
reduced pressure and the residue was purified by flash chromatography on silica gel
(EtOAc/PE ¼ 1:10) to gave the desired compound 8 as a colourless oil (0.3 g, 90%
1
yield). H NMR (400 MHz, CDCl3): d 6.74 (dd, J ¼ 8.7, 4.9 Hz, 2H), 6.71 (s, 1H), 4.19-4.09
(m, 4H), 3.83 (s, 3H), 3.82 (s, 3H), 3.60 (dd, J ¼ 17.0, 9.2 Hz, 1H), 3.14 (d, J ¼ 7.8 Hz, 2H),
1.30-1.14 (m, 6H).
3.2.2. 2-(3,4-Dimethoxybenzyl)propane-1,3-diol (5)
To a suspension of LiAlH4 (0.0053 g, 0.14 mmol) in THF (0.6 mL) was slowly added the
solution of 8 (0.0218 g, 0.07 mmol) in THF (0.6 mL) at 0 ꢀC, and the mixture was stirred
for 4 h at room temperature. Then the reaction was quenched by addition of methanol
(1.0 mL), 15% NaOH aqueous solution (1.0 mL) and water (5.0 mL) at 0 ꢀC. The mixture
was acidified by 2 M HCl and extracted with EtOAc (3 ꢃ 10 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2 ¼ 1:20) to
1
give the compound 5 as a colourless oil (0.014 g, 87% yield). H NMR (400 MHz, CDCl3)
d 6.79 (d, J ¼ 9.9 Hz, 1H), 6.72 (d, J ¼ 4.9 Hz, 2H), 3.86 (dd, J ¼ 3.7, 1.6 Hz, 6H),
3.83 ꢁ 3.78 (m, 2H), 3.7.-3.65 (m, 2H), 2.57 (dd, J ¼ 7.4, 2.7 Hz, 2H), 2.35 ꢁ 2.12 (m, 2H),
2.07-2.02 (m, 1H), 1.30 ꢁ 1.20 (m, 1H).
3.2.3. (R)-2-(3,4-dimethoxybenzyl)-3-hydroxypropyl acetate (4)
Lipase PS (0.5 g) was added to a solution of 5 (0.5 g, 2.21 mmol) in vinyl acetate
(20 mL) at room temperature in one portion. The resulting suspension was magnetic-
ally stirred at room temperature for 3 h. Then the mixture was filtrated through sand
core funnel. The filtrate was condensed in vacuo to provide the crude residue, which
was purified using flash silica gel chromatography (EtOAc/PE ¼ 2:1) to provide 4 as a
colourless oil. (0.587 g, 99% yield, 96% ee). The ee value of (R)-4 was determined with
HPLC fOJ-H, hexane/2-propanol ¼ 4:1 (v/v)g. [a]2D5 ¼ þ23.0 (c ¼ 1.48 in CH2Cl2);1H
NMR (400 MHz, CDCl3): d 6.77 (d, J ¼ 8.1 Hz, 1H), 6.70 (d, J ¼ 5.73 Hz, 2H), 4.16 (dd,
J ¼ 11.2, 4.6 Hz, 1H), 4.06 (dd, J ¼ 11.2, 6.5 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.58 (dd,
J ¼ 11.3, 4.6 Hz, 1H), 3.50 (dd, J ¼ 11.3, 6.1 Hz, 1H), 2.59 (m, 3H), 2.07 (s, 4H). 13C NMR
(100 MHz, CDCl3): d 171.90, 149.02, 147.99, 131.98, 121.16, 112.28, 111.35, 64.16, 62.12,
56.04, 55.97, 42.64, 34.01, 21.07. HRMS (ESI) calcd for C14H21O5 [M þ H]þ 269.1389,
found 269.1388.

NATURAL PRODUCT RESEARCH
7
3.2.4. (S)-2-(3,4-dimethoxybenzyl)-3-(3-methoxyphenoxy)propyl acetate (3)
To a stirred solution of 1,10-(azodicar-bonyl)dipiperidine (0.6827 g, 2.71 mmol) in anhyd-
rous THF (6 mL) was added dropwise Bu3P (0.77 mL, 3.07 mmol) over 5 min. The result-
ing mixture was stirred for 0.5 h until the solution turned colorless. At this point, a
solution of 4 (0.33 g, 1.23 mmol) in anhydrous THF (6 mL) followed by a solution of 3-
methoxyphenol (0.1 mL, 1.00 mmol) in anhydrous THF (6 mL) were added dropwise.
Then the reaction was warmed up to 70 ꢀC and stirred for another 12 h at this tem-
perature. The solvent was removed in vacuo, and the residue was rapidly purified on a
short silica gel chromatography (EtOAc/PE ¼ 1:5) to produce the desired compound 3
as a colorless oil (0.3620 g, 87% yield). [a]2D5 ¼ ꢁ31.1 (c ¼ 0.76 in CH2Cl2); 1H NMR
(400 MHz, CDCl3): d 7.16 (t, J ¼ 8.2 Hz, 1H), 6.78 (d, J ¼ 6.57 Hz, 1H), 6.71 (dd, J ¼ 8.1,
1.9 Hz, 1H), 6.67 (d, J ¼ 1.9 Hz, 1H), 6.52-6.44 (m, 3H), 4.23-4.13(m, 2H), 3.91-3.83 (m,
5H), 3.78 (s, 3H), 3.75 (s, 3H), 2.81-2.70 (m, 2H), 2.42-2.35 (m, 1H), 2.07 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 171.23, 161.01, 160.25, 149.00, 147.64, 131.57, 130.07,
121.26,112.42, 111.36,106.85, 106.53, 101.13, 66.65, 64.48,56.05, 55.85, 55.45, 40.15,
34.15, 21.13. HRMS (ESI) calcd for C21H27O6 [M þ H]þ 375.1808, found 375.1808.
3.2.5. (R)-2-(3,4-dimethoxybenzyl)-3-(3-methoxyphenoxy)propan-1-ol (9)
Compound 3 (0.2746 g, 0.81 mmol) was dissolved in MeOH (5 mL), and anhydrous
K2CO3 (0.1683 g, 1.22 mmol) was added. The suspension was stirred at room tempera-
ture for 4 h. The reaction was poured into H2O and extracted with EtOAc (3 ꢃ 5 mL).
The collected phase was dried over anhydrous Na2SO4, filtered, and concentrated. The
residue was purified by silica gel chromatography (EtOAc/PE ¼ 1:3) to afford 9 as a a
colourless oil (0.2401 g, 89% yield). [a]2D5 ¼ ꢁ46.92 (c ¼ 0.65 in CH2Cl2);1H NMR
(400 MHz, CDCl3): d 7.16 (t, J ¼ 8.2 Hz, 1H), 6.78 (d, J ¼ 8.0 Hz, 1H), 6.72 (dd, J ¼ 10.4,
2.2 Hz, 2H), 6.52-6.44 (m, 3H), 3.97 (dd, J ¼ 9.2, 4.5 Hz, 1H), 3.91 (dd, J ¼ 9.2, 5.9 Hz, 1H),
3.84 (s, 3H), 3.80-3.71 (m, 8H), 2.74 (d, J ¼ 7.0 Hz, 2H), 2.29-2.19 (m, 1H); 13C NMR
(100 MHz, CDCl3): d 160.97, 160.17, 148.96, 147.51, 132.25, 130.08, 121.17, 112.40,
111.31, 106.85, 106.59, 101.09, 68.36, 63.88, 56.02, 55.84, 55.42, 42.90, 34.01. HRMS
(ESI) calcd for C19H25O5 [M þ H]þ 333.1702, found 333.1702.
3.2.6. (6ar,11bR)-3,9,10-trimethoxy-6,6a,7,11b-tetrahydroindeno[2,1-c]chromene (1)
To a stirred solution of 9 (0.1484 g, 0.45 mmol) in CH2Cl2 (3 mL), NaHCO3 (0.1313 g,
1.56 mmol) and Dess-Martin periodinane (0.38 g, 0.9 mmol) was added. The reaction
was stirred for 3 h at room temperature. Then hexane was added, and the mixture
was washed with CH2Cl2 (3 ꢃ 5 mL). The insoluble material was removed by filtration.
The solution was concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (EtOAc/hexane ¼ 1:3) to give (0.1224 g, 83%
yield) of the compound 2, which was then subjected to the next cyclisation immedia-
tely.p-toluenesulfonic acid (1.35 g, 7.11 mmol) was added to the solution of 2 (0.47 g,
1.42 mmol) in CH2Cl2 (6 mL) at room temperature. The mixture was then stirred for 1 h
at room temperature and quenched with saturated aq. NaHCO3 (2 mL). The mixture
was extracted with CH2Cl2 (3 ꢃ 10 mL) and washed with brine. The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. Compound 1 was obtained
as a white solid (0.24 g, 51% yield) after silica gel flash chromatography (EtOAc/PE ¼

8
X. GUO ET AL.
1
1:10). mp: 55.2-56.6 ꢀC . [a]D25 ¼ ꢁ131.2 (c ¼ 0.48 in CH2Cl2); H NMR (400 MHz, CDCl3):
d 7.32 (d, J ¼ 8.5 Hz, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.60 (dd, J ¼ 8.4, 2.6 Hz, 1H), 6.43 (d,
J ¼ 2.5 Hz, 1H), 4.23 (d, J ¼ 6.5 Hz, 1H), 4.13 (dd, J ¼ 10.9, 4.4 Hz, 1H), 3.87 ꢁ 3.84 (m,
6H), 3.77 (s, 3H), 3.63 (t, J ¼ 10.6 Hz, 1H), 3.18 (dd, J ¼ 15.7, 7.2 Hz, 1H), 2.92 (tdd,
J ¼ 6.4, 4.2, 2.0 Hz, 1H), 2.60 (dd, J ¼ 15.7, 2.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
199.31, 155.73, 148.99, 148.38, 137.45, 132.80, 130.87, 116.08, 108.56, 108.15, 108.01,
102.00, 67.04, 56.29, 56.24, 55.50, 43.40, 37.07, 34.22, 29.91. HRMS (ESI) calcd for
C19H21O4 [M þ H]þ 313.1440, found 313.1440.
3.2.7. (–)-Brazilane
To a solution of compound 1 (0.1 g) in CH2Cl2 was dropwise added BBr3 (1 M in
CH2Cl2, 1.53 mL, 1.53 mmol) at ꢁ78 ꢀC. After being stirred at ꢁ78 ꢀC for 2 h, the reac-
tion mixture was stirred at room temperature for another 5 h. The mixture was
quenched with H2O and extracted with EtOAc (3 ꢃ 10 mL) . The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by
silica gel flash chromatography (EtOAc/PE/CH2Cl2¼ 1:1:1) to give (–)-brazilane (0.055 g,
63% yield, 96% ee) as a red solid. The ee value was determined with HPLC fAD-H col-
umn, hexane/MeOH ¼ 20:3 (v/v), 0.5 mL/min, 214 nmg . mp: 157-159 ꢀC. [a]D25 ¼ ꢁ81.3
1
(c ¼ 0.17 in MeOH); H NMR (400 MHz, CD3OD): d 7.16 (d, J ¼ 8.3 Hz, 1H), 6.73 (s, 1H),
6.60 (s, 1H), 6.40 (dd, J ¼ 8.3, 2.5 Hz, 1H), 6.20 (d, J ¼ 2.5 Hz, 1H), 4.07-3.98 (m, 2H), 3.45
(t, J ¼ 10.6 Hz, 1H), 3.02 (dd, J ¼ 15.6, 7.1 Hz, 1H), 2.77-2.71 (m, 1H), 2.44 (dd, J ¼ 15.6,
1.9 Hz, 1H). 13C NMR (100 MHz, MeOD): d 157.73, 156.79, 145.47, 145.20, 138.37, 133.25,
132.16, 116.76, 112.98, 112.63, 109.67, 104.33, 67.88, 44.28, 38.43, 34.63. HRMS (ESI)
calcd for C16H15O4 [M þ H]þ 271.0970, found 271.0968.
4. Conclusions
In conclusion, we have accomplished an efficient synthetic route toward the stereo-
selective total synthesis of (–)-brazilane, in which a lipase-catalyzed desymmetrisation
reaction to prepare a chiral primary alcohol using vinyl acetate was the key step. This
chiral center controlled the subsequent one-pot intramolecular tandem Prins/Friedel-
Crafts reaction to construct the cis-fused chromane and indane framework. This
approach showed an alternative synthetic strategy towards brazilane, especially for
similar compounds containing the cis-fused chromane and indane framework. Further
studies on the applications of this approach to natural products and pharmaceuticals
are in currently in progress in our laboratory and will be disclosed in due course.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the National Natural Science Foundation of China (No. 82003810,
21062088), Natural Science Foundation of Jiangxi Province (No. 20161BAB204189) and Research
funds for outstanding doctors from Shanxi provincial finance.

NATURAL PRODUCT RESEARCH
9
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